Objective-To investigate whether and how the endoplasmic reticulum (ER) stress-induced, CCAAT/enhancer-binding protein-homologous protein (CHOP)-mediated pathway regulates myocardial ischemia/reperfusion injury. Methods and Results-Wild-type and chop-deficient mice underwent 50 minutes of left coronary artery occlusion followed by reperfusion. Expression of chop and spliced x-box binding protein-1 (sxbp1) mRNA was rapidly and significantly increased in reperfused myocardium of wild-type mice. chop-deficient mice exhibited markedly reduced injury size after reperfusion compared with wild-type mice, accompanied by a decreasing number of terminal deoxynucleotidyl transferase dUTP nick-end labeling-positive cardiomyocytes. Interestingly, myocardial inflammation, as assessed by expression of inflammatory cytokines and chemokines and numbers of infiltrated inflammatory cells, was also attenuated in chop-deficient mice. Moreover, expression of interleukin-6 mRNA in response to lipopolysaccharide was enhanced by simultaneous stimulation with thapsigargin, a potent ER stressor, in wild-type cardiomyocytes but not in chop-deficient cardiomyocytes. Finally, we found that superoxide was produced in reperfused myocardium and that intravenous administration of edaravone, a free radical scavenger, immediately before reperfusion significantly suppressed the superoxide overproduction and subsequent expression of sxbp1 and chop mRNA, followed by reduced injury size in wild-type mice. Conclusion-The ER stress-induced, CHOP-mediated pathway, which is activated in part by superoxide overproduction after reperfusion, exacerbates myocardial ischemia/reperfusion injury by inducing cardiomyocyte apoptosis and myocardial inflammation. Key Words: ischemic heart disease Ⅲ reactive oxygen species Ⅲ reperfusion injury Ⅲ CHOP Ⅲ ER stress T he endoplasmic reticulum (ER), one of the largest cellular organelles, is recognized as the principal site of synthesis, folding, assembly, and modification of numerous proteins. Various pathophysiological stimuli, which increase the demand for protein folding or disrupt folding capacity, cause accumulation of unfolded or misfolded proteins within the ER, a condition collectively known as ER stress. To overcome ER stress, cells activate specific signaling pathways in what is termed the ER stress response, the initial intent of which is to restore ER homeostasis and promote cell survival through alteration of cellular transcriptional and translational programs. However, if restoration fails, ER stress triggers a final response, namely, apoptosis, to protect the organism by eliminating damaged cells. Induction of C/EBP-homologous protein (CHOP), a member of the C/EBP transcription factor family, is a signaling event underlying ER stress-induced apoptosis, 1-3 and the involvement of CHOPmediated apoptosis has been demonstrated in various diseases, including diabetes, neurodegenerative diseases, brain ischemia, and even some cardiovascular diseases. [3][4][5] In the setting of acute myocardial infarction, early...

Expression of podoplanin in AMs is considered to be associated with neoplastic odontogenic tissues; this molecule might play a role in the collective cell migration of tumor nests in AMs. The pattern of expression of E-cadherin and vimentin suggests that invasion in AMs occurs in the absence of EMT. The migration and invasion mediated by podoplanin in AMs could be related to cytoskeletal reorganization.

Human podoplanin, a type-1 transmembrane sialomucin-like glycoprotein, is involved in cell migration, tumor cell invasion, and metastasis. However, the role of the protein in squamous cell carcinoma (SCC) has been unclear and immunohistochemical reactivity for podoplanin differs from organ-to-organ. In the present study, immunohistochemical and molecular biological analyses were performed to examine the importance of podoplanin expression in oral precancerous and cancerous lesions and metastases. We immunohistochemically investigated the expression of podoplanin in 103 precancerous lesions, 69 primary oral squamous cell carcinomas (OSCCs), and 32 metastases, and that of E-cadherin and vimentin in primary OSCCs with metastasis. Furthermore, human OSCC-derived cell lines preincubated with fibrous growth factor-basic, epidermal growth factor (EGF), and tumor growth factor-β1 were subjected to real-time reverse transcription polymerase chain reaction. Immunoreactivity for podoplanin was detected in 89 (86.4%) of the precancerous lesions and the intensity was correlated with the degree of epithelial dysplasia (P = 0.016). Enhanced podoplanin expression was observed in 66 (95.7%) of the OSCCs and was significantly associated with a poor pathologic grade of differentiation (P = 0.020). Epithelial-mesenchymal transition was observed in 18 (58.1%) of the primary OSCCs with metastasis to regional lymph nodes. Messenger RNA for podoplanin was markedly increased after treatment with EGF in three OSCC cell lines. The present findings suggest that podoplanin is associated with tumor development via the oral dysplasia-carcinoma sequence and could be involved in a signaling pathway governing tumor growth and invasion in OSCC.

A relationship between Epstein-Barr virus (EBV) infection and cancer of lymphoid and epithelial tissues such as Burkitt's lymphoma, Hodgkin's disease, nasopharyngeal carcinoma (NPC), gastric carcinoma, and oral cancer has been reported. EBV is transmitted orally and infects B cells and epithelial cells. However, it has remained uncertain whether EBV plays a role in carcinogenesis of oral mucosal tissue. In the present study, we detected the EBV genome and latent EBV gene expression in normal mucosal epithelia, epithelial dysplasia, and oral squamous cell carcinoma (OSCC) to clarify whether EBV is involved in carcinogenesis of the oral cavity. We examined 333 formalin-fixed, paraffin-embedded tissue samples (morphologically normal oral mucosa 30 samples, gingivitis 32, tonsillitis 17, oral epithelial dysplasia 83, OSCC 150, and NPC 21). EBV latent infection genes (EBNA-2, LMP-1) were detected not only in OSCC (50.2 %, 10.7 %) but also in severe epithelial dysplasia (66.7 %, 44.4 %), mild to moderate epithelial dysplasia (43.1 %, 18.5 %), gingivitis (78.1 %, 21.9 %), and normal mucosa (83.3 %, 23.3 %). Furthermore, the intensity of EBV latent infection gene expression (EBER, LMP-1) was significantly higher in severe epithelial dysplasia (94.4 %, 72.2 %) than in OSCC (34.7 %, 38.7 %). These results suggest that EBV latent infection genes and their increased expression in severe epithelial dysplasia might play an important role in the dysplasia-carcinoma sequence in the oral cavity.

Podoplanin is strongly expressed in KCOTs in comparison with OOCs. The pattern of staining for podoplanin in KCOT could be related to its neoplastic nature, and suggests a role of the protein in tumor invasiveness.

SUMMARYThis paper reviews conventional wrinkle models for anisotropic membrane and shows the relation between the models. A new wrinkle model is proposed which assumes virtual shear as well as virtual elongation of the membrane to estimate the real strain in the wrinkled region. This model coincides with the other models if the virtual shear and elongation is determined so that the strain energy is minimized. Another wrinkle/slack model is proposed for the dynamic analysis of thin isotropic membrane undergoing large overall motion with wrinkle and slack. It can take into account the residual compressive stress in the wrinkled and slack regions, i.e. the stiffness in the post-buckling state. It is shown that the proposed model is a generalization of the conventional ones. Finite element formulation of the proposed model is described. Furthermore, the energy momentum conservation framework is constructed for the proposed membrane element, which achieves the unconditionally stable time integration. The total of the proposed method enables us to compute the overall motion of thin isotropic membrane such as the deployment of folded membrane, which has been one of the most difficult problems in aerospace engineering.

Patients affected by autoimmune diseases (rheumatoid arthritis, psoriasis, dermatomyositis) who are treated with methotrexate (MTX) sometimes develop lymphoproliferative disorders (LPDs). In approximately 40% of reported cases, the affected sites have been extranodal, and have included the gastrointestinal tract, skin, lung, kidney, and soft tissues. However, MTX-associated LPD (MTX-LPD) is extremely rare in the oral cavity. Here we report a 69-year-old Japanese woman with rheumatoid arthritis (RA) who developed MTX-LPD resembling Hodgkin's disease--so-called "Hodgkin-like lesion"--in the left upper jaw. Histopathologically, large atypical lymphoid cells including Hodgkin or Reed-Sternberg-like cells were found to have infiltrated into granulation tissue in the ulcerative oral mucosa. Immunohistochemistry showed that the large atypical cells were positive for CD20, CD30 and Epstein-Barr virus (EBV)-latent infection membrane protein-1 (LMP-1) and negative for CD15. EBV was detected by in situ hybridization (ISH) with EBV-encoded small RNA (EBER), and polymerase chain reaction (PCR) for LMP-1 and EBNA-2 in material taken from the formalin-fixed, paraffin-embedded specimen. To our knowledge, this is the first reported case of MTX-related EBV-associated LPD (MTX-EBVLPD), "Hodgkin-like lesion", of the oral cavity in a patient with RA.

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